The present application relates to formulations and methods for stabilizing viruses used in vaccines, particularly vaccines for influenza and measles. The application further relates to dry solid formulations of influenza and measles vaccines suitable for use in dissolvable microneedles or coated microneedles.
World Health Organization (WHO) statistics indicate that millions of people suffer from communicable diseases each year. For example, influenza is estimated to cause severe illness in 3 to 5 million people annually and results in as many as 250,000 to 500,000 deaths. Measles is estimated to infect more than 20 million people annually and results in over 150,000 deaths (mostly children under the age of five). The primary way to prevent these infections is successful vaccination campaigns.
For example, WHO estimates that interruption of measles transmission requires vaccine coverage rates in excess of 90%. This high bar requires a potent vaccine and a coordinated effort between vaccine manufacturers, public health experts, and health care personnel that administer the vaccines in the field. Thus, there are numerous obstacles that make the widespread dissemination of such vaccines more difficult.
Although a live measles vaccine has been available since the early 1960s, and is extremely effective when given correctly, storage requirements can impede its widespread dissemination as it is regarded as one of the more unstable live vaccines approved for human use. WHO estimates that more than 60% of the measles vaccine stock delivered into the field cannot be utilized due to spoilage, mishandling, or improper reconstitution.
Similar obstacles are faced with influenza vaccines, which currently are only available in liquid formulations that must be maintained at temperatures from 2-8° C. Thus, there is a need for dry solid formulations of vaccines that allow for the production of vaccines that have improved stability, are more easily transported, and are more convenient for mass vaccinations. Despite this need, development of dry vaccine formulations involves numerous variables that need to be considered. See e.g., Chen et al., “Opportunities and challenges of developing thermostable vaccines,” Expert Rev. Vaccines 8(5), 547-557 (2009).
Some of the key considerations involved in preparing dry vaccine formulations include the exposure of virus to various thermal and mechanical stresses and the selection of excipients to minimize those damages. Furthermore, the formulation components must be compatible with the processing method chosen.
Freeze drying and spray drying are two of the widest used methods of drying active pharmaceutical ingredient (API) solutions in the pharmaceutical industry. Freeze drying has been employed to produce several commercial API products, including measles vaccines. The challenges of employing a freeze drying process on a labile biomolecule include the exposure of the virus to low temperature, adsorption of viral particles to ice crystal surface, and dehydration stress, to name a few.
Spray drying provides advantages of offering high volume product throughput (>5,000 lb/hr) and reduced manufacturing times over other protein preservation/drying technologies such as freeze drying. The challenge of using spray drying to stabilize thermally labile APIs, such as viruses, involves the control of three key areas: atomization conditions, drying conditions, and resultant solid state properties of the dried material. For example, during atomization, the process of breaking up the liquid stream into fine droplets can involve excessive shear stress, surface tension, and pressure applied to the product, leading to loss of bioactivity. Another challenge involves the control of droplet drying rate and its interplay with the components within each droplet. Depending on the process parameters, e.g., the drying rate and the droplet size, and the formulation components, e.g., surface activity and molecular size (i.e., diffusion rate), it is possible to manipulate the properties of the resultant dried particles, which include the particle size, surface composition, and surface morphology. This control is important, as the storage stability of the biopharmaceutical is generally influenced by the degree of its surface enrichment, as well as by the porosity and surface area of the spray dried particles. Numerous disadvantages are therefore associated with the most widely used methods of preparing vaccine formulations, including many disadvantages associated with the most commonly used dehydration techniques.
It therefore would be desirable to provide improved influenza vaccine formulations and improved measles vaccine formulations that are more stable and better suited for mass vaccination by providing simple, convenient, easy-to-administer dosage presentations. It also would be desirable to provide improved methods for preparing dry stable vaccine formulations.